GABA analogs to prevent and treat gastrointestinal damage

ABSTRACT

The present invention is directed to a method for preventing visceral and gastrointestinal damage such as gastric ulcers by administering a gamma-aminobutyric acid (GABA) analog and for treating gastrointestinal diseases such as inflammatory bowel disorders (IBD), functional bowel disorders (FBD) including dyspepsia and other visceral pain.

This application claims priority under 35 U.S.C. 119(e) over provisionalapplications 60/074,794 filed Feb. 16, 1998 and 60/056,753 filed Aug.20, 1997, and is a 371 of PCT/US98/17082 filed Aug. 18, 1998.

FIELD OF THE INVENTION

This invention relates to a method for preventing visceral andgastrointestinal damage such as gastric ulcers by administering agamma-aminobutyric acid (GABA) analog, and for treating gastrointestinaldiseases such as inflammatory bowel disorders (IBD), functional boweldisorders (FBD), including dyspepsia and other visceral pain.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequentlyprescribed drugs for the treatment of pain associated withosteoarthritis and many other musculoskeletal and inflammatorydisorders. In the United States, about 100 million prescriptions arewritten each year to provide effective relief of pain and treatment ofinflammatory diseases. Commonly used NSAIDs include sulindac, naproxen,indomethacin, mefenamic acid, diclofenac, fenoprofen, and diflunisal.

However, considerable evidence indicates that NSAIDs have frequent,serious, and costly gastrointestinal tract toxic side effects. Theseinclude mild dyspepsia, gastritis, peptic ulcer disease, as well as moreserious gastrointestinal complications such as bleeding and perforation,leading sometimes to significant morbidity and, to a lesser extent,mortality. Serious GI complications due to NSAID use represent thegreatest threat to life in patients with connective tissue diseases,second only to the primary disease and its complications. Similargastrointestinal damage is caused by ingestion of alcohol. Indeed, acondition known as ethanol withdrawal syndrome is commonly encounteredwhen prolonged ethanol consumption is terminated. In addition togastrointestinal damage, this syndrome often results in tremors,anxiety, convulsions, hallucinations, and confusion.

Other commonly encountered gastrointestinal disorders includeinflammatory bowel disorders (IBD) and functional bowel disorders (FBD),including dyspepsia. These GI disorders include a wide range of diseasestates that are currently only moderately controlled, including Crohn'sdisease, ileitis, ischemic bowel disease, and ulcerative colitis, aswell as IBD, the irritable bowel syndrome, dyspepsia, andgastro-esophageal reflux for FBD, and other forms of visceral pain.

Gamma-aminobutyric acid has been shown to activate gastric afferentnerves which, in turn, have been shown to participate in gastric defensemechanisms. We have now discovered that GABA analogs dramatically reducethe gastrointestinal damage caused by drugs and alcohol. The GABAanalogs also treat the conditions resulting from ethanol withdrawalsyndrome, and GI disorders characterized as IBD and IBS.

All that is required to prevent gastrointestinal damage and to treatIBD, IBS, and alcoholism according to this invention is to administer toa subject who is in need of treatment an effective amount of a GABAanalog.

Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is nowcommercially available and extensively used clinically for treatment ofepilepsy and neuropathic pain. Such compounds are described in U.S. Pat.No. 4,024,175. Another series of GABA analogs which are anti-seizureagents is described in U.S. Pat. No. 5,563,175.

SUMMARY OF THE INVENTION

This invention provides a method for preventing and treatinggastrointestinal damage and disorders comprising administering to asubject in need of treatment an effective amount of a GABA analog. Apreferred embodiment utilizes a cyclic amino acid compound of Formula I##STR1## wherein R₁ is hydrogen or lower alkyl and n is an integer offrom 4 to 6, and the pharmaceutically acceptable salts thereof. Anespecially preferred embodiment utilizes a compound of Formula I whereR₁ is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexaneacetic acid, known generically as gabapentin. Other preferred GABAanalogs have Formula I wherein the cyclic ring is substituted, forexample with alkyl such as methyl or ethyl. Typical compounds include(1-aminomethyl-3-methylcyclohexyl)acetic acid,(1-aminomethyl-3-methylcyclopentyl)acetic acid, and(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.

In another embodiment, the method of the invention utilizes a GABAanalog of Formula II ##STR2## or a pharmaceutically acceptable saltthereof, wherein R₁ is a straight or branched alkyl of from 1 to 6carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;

R₂ is hydrogen or methyl; and

R₃ is hydrogen, methyl, or carboxyl.

Diastereomers and enantiomers of compounds of Formula II can be utilizedin the invention.

An especially preferred method of the invention employs a compound ofFormula II where R₂ and R₃ are both hydrogen, and R₁ is --(CH₂)₀₋₂ -i C₄H₉ as an (R), (S), or (R,S) isomer.

A more preferred embodiment of the invention utilizes3-aminomethyl-5-methyl-hexanoic acid, and especially(S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically aspregabalin, as well as CI-1008. Another preferred compound is3-(1-aminoethyl)-5-methylhexanoic acid.

The invention additionally provides a composition comprised of ananti-inflammatory amount of an NSAID and a cytoprotective amount of aGABA analog.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the method of this invention utilizes any GABA analog. AGABA analog is any compound derived from or based upongamma-aminobutyric acid. The compounds are readily available, eithercommercially, or by synthetic methodology well-known to those skilled inthe art of organic chemistry. The preferred GABA analogs to be utilizedin the method of this invention are cyclic amino acids of Formula I.These are described in U.S. Pat. No. 4,024,175, which is incorporatedherein by reference. Another preferred method utilizes the GABA analogsof Formula II, and these are described in U.S. Pat. No. 5,563,175 whichis incorporated herein by reference.

All that is required to practice the method of preventing and treatinggastrointestinal damage and disorders of this invention is to administera GABA analog in an amount that is effective to prevent or treat thedamage condition, i.e., to combat the effects of a NSAID or alcohol, orto control IBD and IBS. The invention includes a method for treatingethanol withdrawal syndrome and general alcoholism. The effective amountof GABA analog to be utilized will generally be from about 1 to about300 mg per kg of subject body weight. Typical doses will be from about10 to about 5000 mg per day for an adult subject of normal weight.

Typical "gastrointestinal damage" conditions caused by NSAID use includedyspepsia, gastritis, peptic ulcer, as well as lower gastrointestinalbleeding and perforation. Further effects of ethanol withdrawal syndromeinclude tremor, anxiety, and convulsions. Typical IBD conditions includeileitis, ulcerative colitis, and Crohn's disease.

Pharmaceutical compositions of the compound of the present invention orits salts are produced by formulating the active compound in dosage unitform with a pharmaceutical carrier. Some examples of dosage unit formsare tablets, capsules, pills, powders, aqueous and nonaqueous oralsolutions and suspensions, and parenteral solutions packaged incontainers containing either one or some larger number of dosage unitsand capable of being subdivided into individual doses. Some examples ofsuitable pharmaceutical carriers, including pharmaceutical diluents, aregelatin capsules; sugars such as lactose and sucrose; starches such ascorn starch and potato starch, cellulose derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose, methyl cellulose, andcellulose acetate phthalate; gelatin; talc; stearic acid; magnesiumstearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil,olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin;sorbitol; polyethylene glycol; water; agar; alginic acid; isotonicsaline, and phosphate buffer solutions; as well as other compatiblesubstances normally used in pharmaceutical formulations. Thecompositions of the invention can also contain other components such ascoloring agents, flavoring agents, and/or preservatives. Thesematerials, if present, are usually used in relatively small amounts. Thecompositions can, if desired, also contain other therapeutic agents. Foruse in combating the gastrointestinal effects of NSAIDs, the GABAanalogs can be administered alone in unit dosage form, or in combinationwith the NSAID being utilized for the particular patient.

The percentage of the active ingredient in the foregoing compositionscan be varied within wide limits, but for practical purposes it ispreferably present in a concentration of at least 10% in a solidcomposition and at least 2% in a primary liquid composition. The mostsatisfactory compositions are those in which a much higher proportion ofthe active ingredient is present, for example, from 10% to 90% byweight.

Routes of administration of the subject compound or its salts are oralor parenteral. For example, a useful intravenous dose is between 5 and50 mg and a useful oral dosage is between 20 and 800 mg. The dosage iswithin the dosing range used in treatment of gastrointestinal diseasessuch as ulcers and IBS, or as would be dictated by the needs of thepatient as described by the physician.

A unit dosage form of the GABA analog to be used in this invention mayalso comprise other compounds useful in the therapy of gastrointestinaldiseases.

The advantages of using the compounds of Formula I and II, especiallygabapentin and pregabalin, in the instant invention include therelatively nontoxic nature of the compounds, the ease of preparation,the fact that the compounds are well-tolerated, and the ease of IV andoral administration of the drugs. Further, the drugs are not metabolizedin the body to any great extent.

The subjects as used herein are mammals, including humans.

The invention also provides a composition comprising an NSAID(non-steroidal anti-inflammatory drug) together with a GABA analog. TheNSAID will be present in an anti-inflammatory amount, preferablysomewhat less than normally used, and the GABA analog will be present ina cytoprotective amount, namely an amount which will be effective inpreventing or reducing the gastrointestinal damage otherwise caused bythe NSAID. In general, the NSAID will be present for doses of about 10to about 500 mg, and the GABA analog will be present at about 1 to about1500 mg. Any NSAID can be combined with any GABA analog according tothis invention. Preferred GABA analogs to be employed are the compoundsof Formulas I and II, especially gabapentin and pregabalin. PreferredNSAIDs to be employed in the compositions include sulindac, naproxen,indomethacin, mefenamic acid, diclofenac, fenoprofen, diflunisal,etodolac, ibuprofen, piroxicam, acetylsalicylic acid, oxaprozin, andbromfenac. Most of the NSAIDs to be used are commercially available,generally as salts such as calcium, sodium, or potassium, for example,fensprofen calcium and bromfenac sodium. Especially preferredcombinations include pregabalin or gabapentin, together with naproxensodium or ibuprofen. The compositions may contain common pharmaceuticalexcipients such as those described above.

The ability of GABA analogs to treat gastrointestinal diseases accordingto this invention has been established in several animal models ofinduced gastric lesions and alcoholism.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows the effect of gabapentin on gastric lesions caused byindomethacin.

FIG. 2 shows the effect of gabapentin on handling responses followingwithdrawal of chronic ethanol treatment.

FIG. 3 shows the effect of gabapentin on memory and drowsiness inanimals receiving chronic ethanol treatment.

FIG. 4 shows the effects of gabapentin, CI-1008 (pregabalin), andmorphine on colonic allodynia.

FIG. 5 shows the effects of gabapentin and CI-1008 on colonic painthreshold in rats.

FIGS. 6 and 7 show synergistic effects of gabapentin and naproxenmixtures.

EXAMPLE 1

Gabapentin was evaluated in animals to determine its ability to preventgastric lesions otherwise caused by indomethacin.

Male Sprague-Dawley rats weighing 240 to 250 g were fasted for 24 hoursand allowed free access to water prior to experiment. All test drugswere given intragastrically. Rats were pretreated with different dosesof gabapentin at doses of 40 and 60 mg. Thirty minutes laterindomethacin (25 mg/kg) was administered. Another group of rats received10 mg of gabapentin twice, 3 hours apart, followed by indomethacinadministration. Three hours after indomethacin treatment, the rats werekilled and gastric lesions were assessed. The severity of the lesionswere determined by the measurement of the square area (mm²) of visiblelesions.

Results

1. Indomethacin caused severe gastric hemorrhagic injury; the areas ofinjury were measured at 42.6±5.2 mm² (mean,±standard error of mean).

2. Gabapentin pretreatment significantly reduced indomethacin-inducedgastric injury. The gastric lesion with different doses of gabapentinpretreatment after indomethacin treatment were measured: 22.3±2.8 mm²with 40 mg, 16.5±2.2 mm² with 60 mg/kg, and 4.2±0.39 mm² with 10 mgtwice.

3. Gabapentin pretreatment also dramatically reduced gastric bleeding.

The foregoing data are presented in FIG. 1, where the first bar iscontrol (animals treated with indomethacin alone); Bar 2 is for animalstreated with one dose of 40 mg of gabapentin; Bar 3 is for animals dosedone time with 60 mg of gabapentin; and Bar 4 is for animals dosed twotimes with 10 mg of gabapentin.

EXAMPLE 2

To determine the effects of gabapentin on ethanol-induced gastriclesions, rats were pretreated with 1 mL of 70% aq. ethanol (v/v),followed by gabapentin at a dose of 40 and 60 mg, respectively. Anothergroup of rats were pretreated by 20 mg of gabapentin given twice, 3hours apart, followed by ethanol administration. Thirty minutes later,all rats were killed and gastric lesions were assessed.

Results

1. Seventy percent ethanol induced significant gastric injury. The areaof injury measured 41.9±3.7 mm².

2. Gabapentin pretreatment reduced ethanol-induced gastric injury. With2 doses of 20 mg gabapentin pretreatment, the area of injury measured2.1±0.3 mm². With 40 and 60 mg of gabapentin pretreatment, the area ofinjury measured 24.4±3.5 mm² and 18.7±2.2 mm², respectively.

EXAMPLE 3

The following test in rats was carried out to further establish theability of gabapentin and Pregabalin to reduce the gastrointestinaldamage caused by NSAIDS.

Animals

Male CD-Sprague-Dawley rats (132-202 g) were received and housed in aroom with controlled temperature, humidity, and 12-hour light/darkcycle. After a period of acclimatization of 4 to 5 days, and after a24-hour food fasting period, animals were used for the study describedbelow.

Administration of GABA Analogs and Indomethacin

Gabapentin or pregabalin (CI-1008) were dissolved in water andadministered orally at the following doses: 1, 10, 100, and 200 mg/kg ina volume of 1 mL. Control animals were dosed with an equal volume ofvehicle (1 mL of water). Sixty minutes later, all the animals received 1mL of a solution of indomethacin dissolved in 5% aqueous NaHCO₃ (80mg/kg). Control animals received 1 mL of 5% aqueous NaHCO₃ orally.Experimental groups were as follows:

    ______________________________________                                        Group     Pretreatment   Damaging Agent                                       ______________________________________                                        Group 1   Water          None (NaHCO.sub.3)                                     Group 2 Water Indomethacin 80 mg/kg                                           Group 3 Gabapentin 1 mg/kg Indomethacin 80 mg/kg                              Group 4 Gabapentin 10 mg/kg Indomethacin 80 mg/kg                             Group 5 Gabapentin 100 mg/kg Indomethacin 80 mg/kg                            Group 6 Gabapentin 200 mg/kg Indomethacin 80 mg/kg                            Group 7 Pregabalin 1 mg/kg Indomethacin 80 mg/kg                              Group 8 Pregabalin 10 mg/kg Indomethacin 80 mg/kg                             Group 9 Pregabalin 100 mg/kg Indomethacin 80 mg/kg                            Group 10 Pregabalin 200 mg/kg Indomethacin 80 mg/kg                         ______________________________________                                    

Evaluation of the Effect

Gastric damage caused by indomethacin correlates with inhibition of thecyclooxygenase product prostaglandin E2 (PGE₂). Animals were sacrificedby decapitation 4 hours post-indomethacin administration. The stomachwas removed and opened along the greater curvature and its imagedigitized and stored on an optical disk using a 486-based PC computerequipped with CUE3 system imaging analysis software (Olympus Corp.,Marietta, Ga., USA). Two 6-mm biopsies were taken from a constant regionof the gastric mucosa located in each side of the glandular portion ofthe stomach, and their PGE₂ content was measured using a commerciallyavailable ELISA kit (Assay Designs Inc., Ann Arbor, Mich., USA). Thepresence of gastric damage was determined using the retrieved electronicimage, and the extent of damage was measured using the CUE3 imagingsoftware. Data are expressed as a percent of gastric area damaged andthe PGE₂ content (pg/mL). The data are present below in Table 1.

                  TABLE 1                                                         ______________________________________                                                                  % Area  PGE.sub.2 Synthesis                           Compound Drug Dose N Damaged (pg/mL)                                        ______________________________________                                        Control   NA       10     0.00 ± 0.00*                                                                       9525.27 ± 156.00*                          Indomethacin ± NA 9 5.56 ± 0.48 1908.03 ± 72.31                      Vehicle                                                                       Indomethacin ± 1 mg/kg 5 2.99 ± 0.46 1783.66 ± 73.47                 Gabapentin                                                                    Indomethacin ± 10 mg/kg 9 3.96 ± 0.35 3065.78 ± 137.19                                                Gabapentin                                   Indomethacin ± 100 mg/kg 10 1.87 ± 0.1 2997.90 ± 226.80                                               Gabapentin                                   Indomethacin ± 200 mg/kg 5 1.43 ± 0.40 2615.74 ± 165.36                                               Gabapentin                                   Indomethacin ± 1 mg/kg 4 8.07 ± 2.19 1209.95 ± 105.50                CI-1008                                                                       Indomethacin ± 10 mg/kg 10 4.07 ± 0.42 2666.16 ± 307.45                                               CI-1008                                      Indomethacin ± 100 mg/kg 10 1.99 ± 0.25* 3994.45 ± 318.95                                             CI-1008                                      Indomethacin ± 200 mg/kg 5 0.34 ± 0.06* 3288.92 ± 407.43                                              CI-1008                                    ______________________________________                                         Values are average ± standard error.                                       *p < 0.05 based on KruskalWallis oneway analysis of variance followed by      Dunn's test and compared to indomethacin group.                          

Both gabapentin and CI-1008 caused a reduction of the amount of gastricdamage induced by indomethacin which, in the case of CI-1008, reachedstatistical significance at doses of 100 and 200 mg/kg.

As expected, the gastric damage caused by indomethacin was associatedwith a significant inhibition of the cyclooxygenase product PGE₂.Neither gabapentin nor CI-1008, at any dose tested, were able tosignificantly modify this effect. This data suggests that thesignificant reduction of the indomethacin-induced gastric damage causedby CI-1008 is not related to an effect of this GABA analog on thecyclooxygenase enzyme.

The foregoing data establish that GABA analogs such as gabapentin andpregabalin are effective in preventing gastrointestinal damage such asgastric lesions, peptic ulcers, and even lower gastrointestinalbleeding, otherwise caused by consumption of alcohol or NSAIDs. The GABAanalogs also treat the effects of alcohol withdrawal, which is asyndrome characterized by tremor, hallucinations, and confusion, andgeneral gastrointestinal disorders such as IBD and IBS.

The following tests establish that GABA analogs are useful to treatethanol withdrawal syndrome.

EXAMPLE 4

Male albino mice of the outbred TO strain (Bantin and Kingman, UK) wereused in all studies. The weight ranged from 25 to 35 g, with no morethan a 5 g range in any single experiment. The mice were housed, eightper cage, at 21° C.±1° C., with 55±10% relative humidity, and a 12-hourlight/dark cycle with the light phase between 09:00 to 21:00. All micereceived ad libitum access to tap water and standard laboratory chow(RM-1, Special Diet Services, UK) until their use in experiments oruntil their diet was replaced with a liquid diet.

Induction of Physical Dependence

Ethanol was administered in a liquid diet schedule. All mice receivedcontrol diet for an initial 2-day period. Ethanol treated mice thenreceived a diet containing 3.5% (v/v) ethanol/water for 2 days, followedby a diet containing 7% ethanol for a further 5 days. The average intakewas 22 to 30 g/kg/day. Control groups were pair-fed a control diet,balanced isocalorifically to match the ethanol containing diet. Therewere no differences in the weights of the ethanol-treated and controlmice at the end of the treatment periods. When mice were withdrawn fromthe ethanol (between 07:00 AM and 09:00 AM), they were provided with tapwater until their use in experiments.

Drug Treatment

Gabapentin was dissolved in saline, the solution being made freshly eachtesting day. Intraperitoneal (i.p.) injections of either gabapentin, 10mL/kg, or saline, were given immediately on withdrawal from the ethanoltreatment in the studies on the handling responses, and 2 hours prior tomeasurement of audiogenic seizures. In the experiments using a standardelevated plus maze, gabapentin or saline was injected i.p. at 8 hoursafter the removal of the ethanol diet, and the mice were placed on theplus maze 60 minutes after the injections. In the studies on motorco-ordination (ataxia) and on locomotor activity, gabapentin or salinewas injected into ethanol-naive chow fed mice immediately beforetesting. Measurements were then made for 60 minutes for the ataxiastudy, and for 30 minutes in the case of the locomotor activity.

Measurement of Handling-Induced Behavior

Following withdrawal from the ethanol treatment at 09:00 AM, ratings ofhandling-induced behavior were assessed by the same experimenter, on thesame mice, every hour for a period of 12 hours after withdrawal fromethanol. Numerical ratings have the definitions shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Behavioral Ratings During Gentle Handling                                     ______________________________________                                        1    Mild tremor on lifting and turning                                         2 Continuous severe tremor on lifting and turning                             3 Clonic forelimb extensor spasm on lifting                                   4 Clonic forelimb extensor spasm on lifting, which continued after                 placing mouse on cage top                                                5 Spontaneous evidence of myoclonic activity followed by (4)                ______________________________________                                    

Each mouse was lifted gently by the tail and held for 3 seconds, 30 cmunder an "Anglepoise lamp" with a 60-watt bulb. The animal was gentlyrotated and its ensuing behavior rated on a scale of 1 to 5 according tothe criteria in Table 2. Groups of 15 mice were used in each of thetreatment groups, and the data were calculated as medians withinterquartile ranges. The data were also expressed as the area under thecurve at 4 and 12 hours from the withdrawal of the ethanol treatment.The results are shown in FIG. 2.

Elicitation of Audiogenic Seizures

At 8 and 12 hours from ethanol withdrawal, the susceptibility tosound-induced convulsions was measured in separate groups of ten mice.Mice were tested individually in a sound-proof perspex box 30×30×30 cmcontaining an electric door-bell. The bell was rung for 2 minutes oruntil the first signs of convulsions. The number of mice which respondedby wild-running and clonic convulsions was counted. The mice werehumanely killed as soon as a full convulsion was seen.

Anxiety-Related Behavior

Mice were withdrawn from the ethanol diet at 7:00 AM and tested foranxiety-related behavior 8 hours later using a murine elevatedplus-maze. It was constructed of perspex with two opposing open arms(30×5×0.25 cm) and two opposing closed arms (30×5×15 cm) which extendedfrom a central platform (5×5 cm). The floor was of matt black perspex.The animals were acclimatized to the experimental room 1 hour prior toexperimentation. Experiments were conducted under dim red light, andeach 5 minute session was video-taped for later analysis, by an observerunaware of the prior treatment. During this analysis (Observer 3.0,Noldus Information Technology, Wageningen, Netherlands) measurementswere made of the time spent on each arm of the maze, the number ofentries onto each arm and rearing activity. The measurements were madein accordance with the definitions in Table 3.

                  TABLE 3                                                         ______________________________________                                        Measurements of Behavior on the Elevated Plus Maze                            ______________________________________                                        Arm entry = All four paws onto either a closed or an open arm.                  "Head Dip" = An exploratory forward head/shoulder movement over the          side of an open arm and down towards the floor.                               "Protected head dips" = Exploratory forward head/shoulder movement            over the side of a closed arm and down towards the floor.                     "Stretch-attend posture" = An exploratory flat body posture where the         mouse stretches forward and then retracts to original position without        moving forward.                                                              ______________________________________                                    

Measurement of Ataxic Actions

Possible ataxic effects of gabapentin were studied in control animals(i.e., not treated with ethanol) by the rotorod method. Mice were placedon a rod rotating at 4.5 rpm, and the time they remained on the rod wasmeasured automatically. A cut-off time of 180 seconds was used in allexperiments. Before the acute drug injections, all mice were tested onthe rotorod to ensure that they stayed on for 180 seconds (a very smallnumber did not do so and were excluded from the studies). Measurementswere made for 60 minutes, at 10-minute intervals, after the acuteadministration of the drug under test. Eight mice were used in eachtreatment group.

Locomotor Activity

The effects of gabapentin in control animals were also tested onlocomotor activity to determine the selectivity of the effects in thewithdrawal studies. Mice were injected with gabapentin solution orsaline and placed immediately in activity test cages crossed byinfra-red beams. The number of infra-red beam breaks was measured every5 minutes for the next 30 minutes. Rearing activity was measured by asimilar set of infrared beams situated 4 cm above the cage floor.

Statistical Analysis

The results of the handling response ratings were compared bynonparametric two-way analysis of variance, designed for repeat measureson the same animal. The results of the area under the curve calculationswere compared by the Mann-Whitney U-test. The convulsion incidence wasanalyzed by Fisher's exact probability test. The measurements from theelevated plus maze were subjected to one-way analysis of variance,followed by a Bonuferroni multiple comparison test, comparing all groupsto the control group which received saline injections, and alsocomparing both ethanol treated groups which received gabapentin to theethanol treated group which received saline. The ataxia measurementswere analyzed by the Mann-Whitney U-test and the locomotor activity byStudent's t-test.

RESULTS

Handling Response

The ratings of behavior in response to gentle handling showed theexpected increase following withdrawal from the ethanol treatment.Gabapentin (GP), at 100 mg/kg (FIG. 2a), significantly reduced thisincrease in ratings when the results were compared over the 12-hourtesting period (p<0.001). The effect of this dose of gabapentin showed amarked reduction in handling scores for around 4 hours. This time periodwas therefore used in later analysis to examine the area under thehandling curve with each dose of the drug. The effects of lower doses ofgabapentin were not significant over the 12-hour period of measurement,but when the areas under the curve were calculated for the first 4 hoursof the study (FIG. 2b), significant effects of the 20- and 50-mg/kgdoses were seen (p<0.05), as well as the 100-mg/kg dose (p<0.01).

Audiogenic Seizures

At the 8-hour time interval, 50 and 100 mg/kg gabapentin decreased theconvulsion incidence after the audiogenic stimulus, with the 100-mg/kgdose reaching statistical significance (p<0.05). There was no effect ofthe lower doses (Table 4). No effect was seen of any of the doses testedat 12 hours from the end of the ethanol treatment (data not shown).

                  TABLE 4                                                         ______________________________________                                        The Effect of Gabapentin on Audiogenic Convulsions Measured                    8 Hours From Ethanol Withdrawal                                                Chronic    Acute         Percentage of Group Showing                                                    Treatment Injection Clonic Convulsions            ______________________________________                                        Control Diet                                                                           Saline        0                                                        Ethanol Diet Saline 80* p < 0.05 c.f.                                           Control/Saline group                                                        Ethanol Diet Gabapentin 5 mg/kg 92                                            Ethanol Diet Gabapentin 20 mg/kg 70                                           Ethanol Diet Gabapentin 50 mg/kg 40                                           Ethanol Diet Gabapentin 100 mg/kg 30 p < 0.01 c.f.                              Ethanol/Saline group                                                      ______________________________________                                    

Elevated Plus Maze

The most prominent effect of ethanol withdrawal in this test was adecrease in the percentage time spent on the open arms of the maze (FIG.3a, F(4,50)=5.12, p<0.002). Gabapentin decreased this effect at both 50and 100 mg/kg. The p values were p<0.05 for the 50-mg/kg dose and p<0.01for 100 mg/kg, for comparison with saline administration in both cases.

Mice undergoing ethanol withdrawal also showed a significant increase inhead dips from the closed arms (protected head dips). This effect wassignificantly reduced by gabapentin at 100 mg/kg (p<0.01 compared withthe effects of saline), as illustrated in FIG. 3b (F(4,50)=6.53,p<0.001). In control animals, the number of protected head dips wassignificantly decreased by gabapentin at 100 mg/kg (p<0.05, comparedwith control values after saline administration). Although the mean timeon the open arms was increased in control animals after this dose ofgabapentin, this was not significantly different from controls withsaline.

EXAMPLE 5

LPS-Colonic Hypersensitivity Assay

The GABA analogs also have been evaluated for their ability to controland treat gastrointestinal disorders characterized as IBD and IBS. Theassay utilized to evaluate the GABA analogs measures the effects ofcompound on lipopolysaccharide-induced delayed rectal allodynia in rats.Intraperitoneal (IP) injections of the endotoxin lipopolysaccharide(LPS) are known to induce long-lasting hyperalgesia in somatic painmodels. The following assay LPS-colonic hypersensitivity assay wasdesigned to evaluate the effect of IP injections of LPS on pain visceralthreshold in an experimental model of rectal distension.

Animal Preparation

Male Wistar rats weighing 250 to 350 g were surgically prepared forelectromyography, according to a standard technique. Rats wereanesthetized by i.p. injection of acepromazine and ketamine (Imalgene1000, Rhone-Merieux, Lyon, France) at doses of 0.6 and 120 mg/kg,respectively. Two groups of four electrodes of nichrome wire (60 cmlength and 80 μm diameter) were implanted bilaterally in the abdominalexternal oblique musculature just superior to the inguinal ligament.Electrodes were exteriorized on the back of the neck and protected by aglass tube attached to the skin. Animals were individually housed inpolypropylene cages and kept in a temperature-controlled room (21° C.).They were allowed free access to water and food (UAR pellets, Epinay,France).

Electromyographic Recording

Electromyographic recording began 5 days after surgery. The electricalactivity of abdominal striated muscles was recorded with anelectroencephalo-graph machine (Mini VIII, Alvar, Paris, France) using ashort-time constant (0.03 sec) to remove low-frequency signals (<3 Hz)and a paper speed of 3.6 cm/minute.

Balloon Distension Procedure

Rats were placed in plastic tunnels (6 cm diameter; 25 cm length) wherethey could not move, escape or turn around, in order to prevent damageto the balloon. They are accustomized to this procedure for 3 or 4 daysbefore rectal distension (RD) in order to minimize stress reactionduring experiments. The animals were determined to be accustomed to theplastic tunnel using two criteria: (i) a behavioral component: when theanimals tried to escape or turn around no more than one time per 5minutes, (ii) the abdominal basal activity: when abdominal striatedmuscles exhibited less than five abdominal contractions per 5 minutes inthe absence of distension. The balloon used for distension was anarterial embolectomy catheter (Fogarty, Edwards Laboratories, Inc.,Santa Ana, USA). Rectal distension (RD) was performed by insertion ofthe balloon (2-mm diameter; 2-cm long) in the rectum, at 1 cm of theanus, the catheter being fixed at the tail. It was inflatedprogressively by steps of 0.4 mL, from 0 to 1.6 mL, each step ofinflation lasting 5 minutes. To detect possible leakage, the volume ofwater introduced in the balloon was checked by complete removal with asyringe at the end of the distension period.

Experimental Protocol

In a first series of experiments, a group of 8 rats were submitted togradual rectal distention. The animals were previously (30 minutes)treated by gabapentin at doses of 30 and 100 mg/kg IP or its vehicle(NaCl 9% aqueous).

In a second series of experiments, the same group of 8 rats received IPlipopolysaccharide (E Coli, serotype 0111:B4) or its vehicle, at a doseof 1 mg/kg IP, 1 hour after a control rectal distension. Then, RD wasperformed 12 hours after LPS injection and was preceded (30 minutes) byIP administration of gabapentin (30 mg/kg) or its vehicle (0.3 mL/rat).

Drugs

LPS was dissolved in saline (NaCl 9%). Intraperitoneal injection ofvehicle was given in a volume of 0.3 mL. LPS was purchased fromSigma-Aldrich (St. Quentin Fallavier, France).

Statistical Analysis

Statistical analysis of the number of abdominal contractions occurringduring each 5-minute period during RD was performed by one-way ANOVAfollowed by Student's paired t-test. Values were expressed as themean±SEM, and differences were considered significant for p<0.05.

The results are presented in Tables 5 and 6, and establish thatgabapentin is effective in reducing lower gastrointestinal disorderssuch as IBS.

                  TABLE 5                                                         ______________________________________                                        Effect of Gabapentin on Abdominal Response Induced by Rectal                    Distension (Number of abdominal contractions/5 minutes; mean ± SEM,       n = 7-8, *p < 0.05, **p < 0.01, significantly different from vehicle;         n % of reduction vs vehicle)                                                   Volume of                                                                              Vehicle    Gabapentin                                                                            Vehicle  Gabapentin                               Distension (0.3 mL/rat) (30 mg/kg) (0.3 mL/rat) (100 mg/kg)                 ______________________________________                                        0.4 mL 4.4 ± 1.6                                                                             5.0 ± 2.1                                                                            3.9 ± 1.8                                                                           2.0 ± 1.4                               0.8 mL 19.1 ± 2.8 10.6 ± 3.4** 19.6 ± 2.3 7.6 ± 3.4**                                                   (-45%)  (-61.2%)                        1.2 mL 23.4 ± 2.6 16.1 ± 2.3* 19.1 ± 2.3 16.7 ± 2.9                                                     (-31.2%)                              ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Effect of Gabapentin on LPS-Induced Delayed (12 Hours) Allodynia                (Number of abdominal contractions/5 minutes; mean, ±SEM, n = 7-8,         +p < 0.001, significantly different from "LPS/vehicle" value; n % of          reduction vs "LPS/vehicle")                                                                               LPS (1 mg/kg) +                                                                Volume of LPS (1 mg/kg) + Gabapentin                                          Distension Vehicle (0.3 mL/rat) (3.0            ______________________________________                                                                     mg/kg)                                           0.4 mL    9.7 ± 1.0   0.7 ± 0.5 + (-92.8%)                                0.8 mL 11.7 ± 1.2 11.9 ± 0.8                                            1.2 mL 23.5 ± 2.2 16.3 ± 3.2                                          ______________________________________                                    

The foregoing experiment was carried out with the GABA-analogpregabalin. Pregabalin, at 30 mg/kg, reduced the number of cramps atboth distension volumes of 0.4 and 0.8 mL. When injected 120 minutesbefore rectal distension, pregabalin, at both 10 and 30 mg/kg, had asimilar effect at all distension volumes. LPS enhanced the number ofabdominal contractions at the volume of 0.4 mL (9.7±1.0 vs. 3.7±1.0) 12hours after its administration. This effect was suppressed when animalsreceived pregabalin (1.8±0.9 vs. 9.7±1.0) at 30 mg/kg 30 minutes priorto rectal distension. These results establish that pregabalin iseffective in reducing basal rectal sensitivity and in blockingLPS-induced rectal allodynia in rats.

EXAMPLE 6

TNBS-Induced Allodynia

GABA analogs were evaluated in rats suffering from chronic visceralallodynia induced by trinitrobenzene sulfonic acid (TNBS). Injections ofTNBS into the colon of animals have been found to induce chroniccolitis. In humans, digestive disorders are often associated withvisceral pain. In these pathologies, the visceral pain threshold isdecreased, indicating a visceral hypersensitivity. Consequently, thefollowing study was designed to evaluate the effect of injection of TNBSinto the colon on visceral pain threshold in an experimental model ofcolonic distension.

Male Sprague-Dawley rats weighing 340 to 400 g were used in the study.The animals were housed three per cage in a regulated environment (20±1°C., 50±5% humidity, with light 8:00 AM to 8:00 PM). Under anethesia(ketamine 80 mg/kg i.p.; acepromazin 12 mg/kg i.p.), TNBS (50 mg/kg), orsaline (1.5 mL/kg) was injected into the proximal colon (1 cm from thececum). After the surgery, animals were individually housed in theregulated environment.

A balloon catheter (5-6 cm length) was inserted through the anus intothe colon and kept in position (tip of balloon 5 cm from the anus) bytaping the catheter to the base of the tail. The balloon wasprogressively inflated by step of 5 mm Hg, from 0 to 75 mm Hg, each stepof inflation lasting 30 seconds. Each cycle of colonic distension wascontrolled by a standard barostat. The threshold corresponds to thepressure which produced the first abdominal contraction, at which timethe cycle of distension was discontinued. To determine the colonicthreshold, four cycles of distension were performed on the same animal.

In a first series of experiments, a group of eight rats treated withsaline were subjected to a colonic distension session.

In a second series, a group of eight rats treated with TNBS weresubjected to a colonic distension session.

In a third series, a group of eight rats treated with TNBS received asubcutaneous (sc) injection of gabapentin or CI-1008 30 minutes prior toinitiation of the colonic distension cycle.

All test compounds were dissolved in saline except TNBS. TNBS wasdissolved in EtOH 30% (w/v). Subcutaneous injection of vehicle was givenin a volume of 2 mg/kg.

Statistical significance between each group was determined using aone-way ANOVA followed by Student's unpaired t-test. Differences wereconsidered statistically significant at p<0.05.

Pain threshold (pressure of distension inducing the first abdominalcontraction) after distal colonic distension was determined at Day 7 intwo groups of awake rats: control animals and TNBS-treated animals. Asignificant decrease in the pain threshold was observed in TNBS-treatedanimals. Inflammatory parameters (colon weight, area of hyperemia andnecrosis and colonic myeloperoxidase content) were measured in theproximal colon at Day 7 after TNBS treatment. All the parameters weresignificantly increased except the area of necrosis.

Gabapentin (100, 300, and 500 mg/kg sc) and CI-1008 (30, 60, 100, and200 mg/kg sc) were administered 30 minutes before colonic distension andmeasurement of the inflammatory parameters. Gabapentin inhibited in adose-related manner the TNBS-induced colonic allodynia. At 500 mg/kg sc,gabapentin completely blocked the effect of TNBS on colonic pain.CI-1008 also showed a dose-related inhibition of the decrease in painthreshold. At 100 mg/kg, CI-1008 completely suppressed the allodyniainduced by TNBS. Morphine (0.1 mg/kg sc) completely suppressed theTNBS-induced decrease in pain threshold after colonic distension (FIG.4). In contrast, neither gabapentin nor CI-1008 inhibited the colonicinflammatory effect of TNBS in these experimental conditions.

In normal conditions (control animals), morphine (0.3 mg/kg sc)significantly increased the colonic pain threshold while, in the sameconditions, neither gabapentin (500 mg/kg sc) nor CI-1008 (200 mg/kg sc)modified the colonic pain threshold (FIG. 5). The results are furthershown in Tables 7 and 8.

                  TABLE 7                                                         ______________________________________                                        Effect of CI-1008, Gabapentin, and Morphine on TNBS-Induced Chronic            Colonic Allodynia in Rats                                                                   Colonic                                                                                                    Threshold                           Treatment (mm Hg)  SEM n p                                                  ______________________________________                                        Control    43.39      ±  1.98    8                                           Sham 33.44 ± 3.25 8 *                                                      TNBS 17.81 ± 1.27 8 ***                                                    CI-1008                                                                       30 mg/kg sc 21.72 ± 1.51 8 ?                                               60 mg/kg sc 25.47 ± 1.03 8 ??                                              100 mg/kg sc 33.13 ± 1.83 8 ???                                            200 mg/kg sc 40.47 ± 3.75 8 ???                                            Gabapentin                                                                    100 mg/kg sc 22.03 ± 2.23 8                                                300 mg/kg sc 24.69 ± 1.27 8 ?                                              500 mg/kg sc 36.88 ± 1.46 8 ???                                            Morphine                                                                      0.1 mg/kg sc 34.22 ± 1.72 8 ???                                            0.3 mg/kg sc 46.09 ± 1.43 8 ???                                            1 mg/kg sc 64.84 ± 1.88 8 ???                                            ______________________________________                                         * = p < 0.05, ** = p < 0.01, and *** = p < 0.001 vs control.                  ? = p < 0.05, ?? = p < 0.01, and ??? = p < 0.001 vs TNBS.                

                  TABLE 8                                                         ______________________________________                                        Effect of CI-1008 and Gabapentin on Colonic Threshold in Normal Rats                         Colonic                                                                                                    Threshold                           Treatment (mm Hg)  SEM n p                                                  ______________________________________                                        Control    43.33      ±  1.23    6                                           CI-1008 46.41 ± 2.26 8 NS                                                  200 mg/kg sc                                                                  Gabapentin 43.75 ± 1.44 6 NS                                               500 mg/kg sc                                                                ______________________________________                                         NS = Not significant vs control.                                         

The foregoing data establish that GABA analogs such as gabapentin andCI-1008 suppress TNBS-induced colonic allodynia, and are thereforeeffective in abnormal colonic hypersensitivity reflecting the chronicpain in IBS.

EXAMPLE 7

Formalin-Induced Inflammatory Colonic Pain

The GABA analogs were evaluated in another model to determine theireffect on inflammatory visceral pain, including pancreatitis andintestinal cystitis.

Administration of formalin into the wall of the rat colon causes acuteinflammation and visceral pain. The aim of this study was to evaluatethe antinociceptive activity of gabapentin and CI-1008 in visceral paininduced by colonic intrapariental injection of formalin.

Adult female Sprague-Dawley rats weighing 240 to 260 g were used in thestudy. The animals were housed three per cage in a regulated environment(20±1° C., 50±5% humidity, with light 8:00 AM to 8:00 PM) prior to usein the test.

Each test animal was placed in a transparent plastic cage (27×43×28 cm)with a layer of wood shavings on the floor. Drinking water wasavailable. Cages were placed in such a way that visual interactionbetween animals was avoided. A mirror was positioned behind each cage toimprove the recording of behaviors. Each animal was initially allowed 20minutes to get used to its surroundings. Anesthesia was then achieved byusing isofurane (starting 4%, then 1.5% in a mixture of 2:3 nitrousoxide and 1:3 oxygen). The animal was suspended by its tail, the rectumwas gently emptied with a cotton-capped stalk, and a coloscope wasinserted through the anus. This designed endoscope has a lateral slotthat allows for puncture of the intestinal wall under visual control,using a 51-mm-long needle (26 ga), at about 35 mm from the anal margin.Injected solutions were either 50 μL 5% aq. formalin (v/v), or the samevolume of isotonic saline. Animals were allowed to recover fromanesthesia as soon as the injection was completed (about 1 minute), andthe observation period was started and continued for 2 hours. Thirtyminutes after the end of the observation test, an IV injection of EvansBlue (1%) was administered, and 30 minutes later the animal wassacrificed. The abdomen was opened. The injection site and the zone ofdiffusion of Evans Blue were recorded by image analysis software. Datafrom rats in which the spread of the dye was not restricted to thesigmoid wall were discarded.

As listed in increasing order of pain intensity, these behaviors were:(i) abdominal licking and nibbling (L), (ii) body stretching, i.e.,backward extension of the hind limbs (B), (iii) contraction of theflanks, sometimes evolving to a stretching attitude (C), and (iv) wholebody contraction, the rat standing with its back curved, occasionallyfurther graded according to the duration of the given episode: W₁ forless than 30 seconds, W₂ between 30 seconds and 1 minute, and W₃ formore than 1 minute. Behaviors were recorded for each animal throughoutthe 2-hour test on individual charts. A pain score (S) was thencalculated for each of the successive 15-minute periods, using thefollowing formula:

    S=1L+2B+3C+4W.sub.1 +5W.sub.2 +6W.sub.3

whereby the pain score was proportional to (i) the number of episodes ofeach selected behavior, and (ii) the coefficient, from 1 to 6,attributed to the given behaviors.

All compounds were dissolved in saline. Subcutaneous injection ofvehicle was given in a volume of 2.5 mg/kg. Formalin was purchased fromProlabo.

Statistical significance between each group was determined by using aone-way ANOVA followed by Student's unpaired t-test. Differences wereconsidered statistically significant at p<0.05.

Hyperalgesia is induced by intramural injection of formalin (5%, 50μL/rat) into the colonic wall in unfasted female Sprague-Dawley rats.Gabapentin and CI-1008 were tested at 100, 300, 500 and 100, 200 mg/kgsc, respectively. Gabapentin and CI-1008 significantly anddose-dependently decreased the pain score induced by intracolonicformalin. The maximal inhibitory effect was observed after 500 mg/kg ofgabapentin and 200 mg/kg of CI-1008. The results are presented in Table9.

This study establishes that GABA analogs exhibit an antinociceptiveeffect on intra-colonic formalin-induced pain, and thus are effective intreating IBD and IBS, and visceral pain, including pancreatitis andintestinal cystitis.

                  TABLE 9                                                         ______________________________________                                        Effect of Subcutaneous Injection of Gabapentin and CI-1008 on                   Inflammatory Colonic Pain Induced by Intramural Injection of                  Formalin 5%                                                                   Treatment   % Antinociception SEM   n    p                                  ______________________________________                                        CI-1008                                                                         100 mg/kg sc 18.55 ±   7.41 7 ***                                          200 mg/kg sc 70.81 ±  7.47 6 ***                                           Gabapentin                                                                    0.3 mg/kg sc -7.73 ± 10.43 3 NS                                            100 mg/kg sc 13.62 ± 12.65 9 NS                                            300 mg/kg sc 55.07 ±  9.98 6 ***                                           500 mg/kg sc 88.01 ± 16.96 6 ***                                         ______________________________________                                         ***                                                                           NS = Not significant vs control.                                         

The following examples further illustrate compositions provided by theinvention which contain a GABA analog in combination with an NSAID.

                  EXAMPLE 8                                                       ______________________________________                                        Tablet Formulation                                                            ______________________________________                                        Naproxen sodium         200 mg                                                  Gabapentin 300 mg                                                             Magnesium stearate  20 mg                                                     Microcrystalline cellulose 100 mg                                             Povidone 100 mg                                                               Talc  50 mg                                                                 ______________________________________                                    

The ingredients are blended to uniformity and pressed into a tablet. Thetablets are administered from 1 to 3 times a day for treatment ofinflammatory conditions such as rheumatoid arthritis, ankylosingspondylitis, osteoarthritis, bursitis, tendinitis, and acute goutyarthritis.

                  EXAMPLE 9                                                       ______________________________________                                        Capsule Formulation                                                           ______________________________________                                        Fenoprofen calcium, USP 150 mg                                                  Pregabalin  50 mg                                                             Cellulose 100 mg                                                              Gelatin  50 mg                                                                Titanium dioxide  10 mg                                                       Cornstarch  50 mg                                                           ______________________________________                                    

The ingredients are blended to uniformity and placed into a gelatincapsule. The capsules are administered from 1 to 4 times a day fortreatment of rheumatoid arthritis and osteoarthritis. The combinationsprovided by this invention comprise an NSAID (eg, naproxen ormeclofenamic acid) and a GABA analog (eg, pregabalin or gabapentin).Such combinations have been shown to be synergistic in their ability totreat pain. For example, gabapentin and naproxen sodium were combined insynergistic amounts and evaluated in a standard rat carrageenan footpadthermal hyperalgesia assay. This assay utilizes an extract of seaweed(carrageenan) that, when injected into the footpad of test animals,causes a sterile inflammation, thereby lowering the pain threshold.Analgesic agents, including GABA analogs such as gabapentin, raise thepain threshold back to normal, thereby enabling the animal to toleratean external source of pain for a longer period of time relative tountreated control animals. Several fixed combinations of gabapentin andnaproxen sodium, ranging in concentrations of about 50 parts by weightof GABA analog to 1 part by weight of NSAID, to 1:1 combinations, wereevaluated in the foregoing assay. The results are shown in FIG. 6 (forfixed 1:1 combinations at various dosages) and in FIG. 7 (for fixed 50:1combinations at various dosages). The data establish that thecombinations of a GABA analog and an NSAID are synergistic in theirability to relieve acute and chronic pain and to induce analgesia.

What is claimed is:
 1. A method for preventing and treatinggastrointestinal damage and disorders comprising administering to asubject in need of treatment an effective amount of a GABA analog.
 2. Amethod according to claim 1 employing a compound of Formula I ##STR3##wherein R₁ is hydrogen or lower alkyl and n is an integer of from 4 to6, and the pharmaceutically acceptable salts thereof.
 3. The methodaccording to claim 2 employing gabapentin.
 4. The method according toclaim 1 employing a compound selected from(1-aminomethyl-3-methylcyclohexyl)acetic acid,(1-aminomethyl-3-methylcyclopentyl)acetic acid, and(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.
 5. A methodaccording to claim 1 employing a compound of Formula II ##STR4## whereinR₁ is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl,or cycloalkyl of from 3 to 6 carbon atoms;R₂ is hydrogen or methyl; andR₃ is hydrogen, methyl, or carboxyl, and the pharmaceutically acceptablesalts thereof.
 6. The method according to claim 5 employing pregabalin.7. The method according to claim 5 employingR-(3)-(aminomethyl)-5-methyl-hexanoic acid.
 8. The method according toclaim 5 employing 3-(1-aminoethyl)-5-methylhexanoic acid.
 9. The methodaccording to claim 1 wherein the gastrointestinal damage is in a subjectwho is receiving or will receive NSIAD therapy or alcohol.
 10. Themethod according to claim 1 wherein the gastrointestinal damage ischaracterized as inflammatory bowel disorder or irritable bowelsyndrome.
 11. The method according to claim 1 wherein the conditiontreated is selected from Crohn's disease, ileitis, ischemic boweldisease, dyspepsia, and ulcerative colitis.
 12. A method for treatingethanol withdrawal syndrome in a mammal in need of treatment comprisingadministering an effective amount of a GABA analog.
 13. A methodaccording to claim 12 employing a compound of Formula I ##STR5## whereinR₁ is hydrogen or lower alkyl and n is an integer of from 4 to 6, andthe pharmaceutically acceptable salts thereof.
 14. The method accordingto claim 13 employing gabapentin.
 15. A method according to claim 12employing a compound of Formula II ##STR6## wherein R₁ is a straight orbranched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl offrom 3 to 6 carbon atoms;R₂ is hydrogen or methyl; and R₃ is hydrogen,methyl, or carboxyl, and the pharmaceutically acceptable salts thereof.16. The method according to claim 15 employing pregabalin.
 17. Apharmaceutical composition comprising a GABA analog and a non-steroidalanti-inflammatory drug together with a pharmaceutically acceptableexcipient, carrier, or diluent therefor.
 18. A composition of claim 17wherein the GABA-analog is a compound of Formula I ##STR7## wherein R₁is hydrogen or lower alkyl and n is an integer of from 4 to 6, and thepharmaceutically acceptable salts thereof.
 19. The composition of claim18 wherein the GABA analog is gabapentin.
 20. A composition according toclaim 17 wherein the GABA analog is a compound of Formula II.
 21. Thecomposition of claim 20 wherein the GABA analog is pregabalin.
 22. Acomposition according to claim 17 wherein the non-steroidalanti-inflammatory drug is selected from sulindac, naproxen,indomethacin, mefenamic acid, diclofenac, fenoprofen, diflunisal,etodolac, ibuprofen, piroxicam, acetylsalicylic acid, oxaprozin, andbromfenac, or pharmaceutical salts thereof.
 23. A composition accordingto claim 22 wherein the non-steroidal anti-inflammatory drug is selectedfrom naproxen sodium, ibuprofen, or indomethacin.
 24. A composition ofclaim 23 comprised of naproxen sodium and pregabalin.
 25. A compositionof claim 23 comprised of naproxen sodium and gabapentin.
 26. Acomposition of claim 23 comprising ibuprofen and pregabalin.
 27. Acomposition of claim 23 comprising ibuprofen and gabapentin.